Pyrimidyl cyclopentanes as akt protein kinase inhibitors

ABSTRACT

The present invention provides compounds of Formula I, including tautomers, resolved enantiomers, diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof. 
     
       
         
         
             
             
         
       
     
     Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

PRIORITY OF INVENTION

This application is a continuation of U.S. patent application Ser. No.13/753,008, filed Jan. 29, 2013, which is a continuation of U.S. patentapplication Ser. No. 12/667,850, filed Jul. 13, 2010, now U.S. Pat. No.8,377,937, which is a 35 U.S.C. 371 national stage application ofInternational Patent Application No. PCT/US2008/069147, filed Jul. 3,2008, and claims priority to U.S. Provisional Application No.60/948,147, filed Jul. 5, 2007, which are hereby incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel inhibitors of serine/threonine proteinkinases (e.g., AKT and related kinases), pharmaceutical compositionscontaining the inhibitors, and methods for preparing these inhibitors.The inhibitors are useful, for example, for the treatment ofhyperproliferative diseases, such as cancer and inflammation, inmammals.

2. Description of the State of the Art

Protein kinases (PK) are enzymes that catalyze the phosphorylation ofhydroxy groups on tyrosine, serine and threonine residues of proteins bytransfer of the terminal (gamma) phosphate from ATP. Through signaltransduction pathways, these enzymes modulate cell growth,differentiation and proliferation, i.e., virtually all aspects of celllife in one way or another depend on PK activity (Hardie, G. and Hanks,S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, SanDiego, Calif.). Furthermore, abnormal PK activity has been related to ahost of disorders, ranging from relatively non-life threateningdiseases, such as psoriasis, to extremely virulent diseases, such asglioblastoma (brain cancer). Protein kinases are an important targetclass for therapeutic modulation (Cohen, P. (2002) Nature Rev. DrugDiscovery 1:309).

Significantly, atypical protein phosphorylation and/or expression isoften reported to be one of the causative effects of abnormal cellularproliferation, metastasis and cell survival in cancer. The abnormalregulation and/or expression of various kinases, including Akt, VEGF,ILK, ROCK, p70S6K, Bcl, PKA, PKC, Raf, Src, PDK1, ErbB2, MEK, IKK, Cdk,EGFR, BAD, CHK1, CHK2 and GSK3 amongst numerous others, has beenspecifically implicated in cancer.

Protein kinases include two classes; protein tyrosine kinases (PTK) andserine-threonine kinases (STK). The Protein Kinase B/Akt enzymes are agroup of serine/threonine kinases that are overexpressed in a variety ofhuman tumors. One of the best-characterized targets of the PI3K lipidproducts is the 57 KD serine/threonine protein kinase Akt, downstream ofPI3K in the signal transduction pathway (Hemmings, B. A. (1997) Science275:628; Hay N. (2005) Cancer Cell 8:179-183). Akt is the humanhomologue of the protooncogene v-akt of the acutely transformingretrovirus AKT8. Due to its high sequence homology to protein kinases Aand C, Akt is also called Protein Kinase B (PKB) and Related to A and C(RAC). Three isoforms of Akt are known to exist, namely Akt1, Akt2 andAkt3, which exhibit an overall homology of 80% (Staal, S. P. (1987)Proc. Natl. Acad. Sci. 84:5034; Nakatani, K. (1999) Biochem. Biophys.Res. Commun. 257:906; Li et al (2002) Current Topics in Med. Chem.2:939-971; WO 2005/113762). The Akt isoforms share a common domainorganization that consists of a pleckstrin homology domain at theN-terminus, a kinase catalytic domain, and a short regulatory region atthe C-terminus. In addition, both Akt2 and Akt3 exhibit splice variants.Upon recruitment to the cell membrane by PtdInd(3,4,5)P₃, Akt isphosphorylated (activated) by PDK1 at T308, T309 and T305 for isoformsAkt1 (PKBα), Akt2 (PKBβ) and Akt3 (PKBγ), respectively, and at S473,S474 and S472 for isoforms Akt1, Akt2 and Akt3, respectively. Suchphosphorylation occurs by an as yet unknown kinase (putatively namedPDK2), although PDK1 (Balendran, A., (1999) Curr. Biol. 9:393),autophosphorylation (Toker, A. (2000) J. Biol. Chem. 275:8271) andintegrin-linked kinase (ILK) (Delcommenne, M. (1998) Proc. Natl. Acad.Sci. USA, 95:11211) have been implicated in this process. Akt activationrequires its phosphorylation on residue Ser 473 in the C-terminalhydrophobic motif (Brodbeck et al (1999) J. Biol. Chem. 274:9133-9136;Coffer et al (1991) Eur. J. Biochem. 201:475-481; Alessi et al (1997)Curr. Biol. 7:261-269). Although monophosphorylation of Akt activatesthe kinase, bis(phosphorylation) is required for maximal kinaseactivity.

Akt is believed to assert its effect on cancer by suppressing apoptosisand enhancing both angiogenesis and proliferation (Toker et al (2006)Cancer Res. 66(8):3963-3966). Akt is overexpressed in many forms ofhuman cancer including, but not limited to, colon (Zinda et al (2001)Clin. Cancer Res. 7:2475), ovarian (Cheng et al (1992) Proc. Natl. Acad.Sci. USA 89:9267), brain (Haas Kogan et al (1998) Curr. Biol. 8:1195),lung (Brognard et al (2001) Cancer Res. 61:3986), pancreatic (Bellacosaet al (1995) Int. J. Cancer 64:280-285; Cheng et al (1996) Proc. Natl.Acad. Sci. 93:3636-3641), prostate (Graff et al (2000) J. Biol. Chem.275:24500) and gastric carcinomas (Staal et al (1987) Proc. Natl. Acad.Sci. USA 84:5034-5037).

The PI3K/Akt/mammalian target of rapamycin (mTOR) pathway has beenexplored for targeted small molecule inhibitor therapy (Georgakis, G.and Younes, A. (2006) Expert Rev. Anticancer Ther. 6(1):131-140;Granville et al (2006) Clin. Cancer Res. 12(3):679-689). Inhibition ofPI3K/Akt signaling induces apoptosis and inhibits the growth of tumorcells that have elevated Akt levels (Kim et al (2005) Current Opinion inInvestig. Drugs 6(12):1250-1258; Luo et al (2005) Molecular Cancer Ther.4(6):977-986).

The development of kinase inhibitors that target abnormally regulatedpathways and ultimately result in disease is of enormous ethical andcommercial interest to the medical and pharmaceutical community. Acompound that inhibits (1) recruitment of Akt to the cell membrane, (2)activation by PDK1 or PDK2, (3) substrate phosphorylation, or (4) one ofthe downstream targets of Akt could be a valuable anticancer agent,either as a stand-alone therapy or in conjunction with other acceptedprocedures.

United States Patent Application Publication 2005/0130954 disclosesinter alia, a variety of compounds that act as AKT inhibitors. Thecompounds are said to be useful in the treatment of hyperproliferativediseases such as cancer.

United States Patent Application Publication 2008/0058327 and UnitedStates Patent Application Publication 2008/0051399 disclose inter alia,a variety of compounds that act as AKT inhibitors.

SUMMARY OF THE INVENTION

This invention provides novel compounds that inhibit AKT proteinkinases. The compounds of the present invention have utility astherapeutic agents for diseases and conditions that can be treated bythe inhibition of AKT protein kinases.

The present invention includes compounds having the general Formula I:

and enantiomers and salts thereof, wherein A, R¹, R^(1a), R², R^(2a),and R³ are as defined below.

The invention also provides pharmaceutical compositions comprising acompound of Formula I, or an enantiomer or pharmaceutically acceptablesalt thereof.

In a further aspect, the present invention provides a method of treatingdiseases or medical conditions in a mammal mediated by AKT proteinkinases, comprising administering to said mammal one or more compoundsof Formula I, or an enantiomer or pharmaceutically acceptable saltthereof, in an amount effective to treat or prevent said disorder. AKTprotein kinase mediated conditions that can be treated according to themethods of this invention include, but are not limited to, inflammatory,hyperproliferative, cardiovascular, neurodegenerative, gynecological,and dermatological diseases and disorders.

In a further aspect, the present invention provides a method ofinhibiting the production of AKT protein kinases in a mammal, whichcomprises administering to said mammal a compound of Formula I, or anenantiomer or pharmaceutically acceptable salt thereof in an amounteffective to inhibit production of an AKT protein kinase.

In a further aspect, the present invention provides methods ofinhibiting the activity of AKT protein kinases, comprising contactingsaid kinase with a compound of Formula I.

The inventive compounds may be used advantageously in combination withother known therapeutic agents. Accordingly, this invention alsoprovides pharmaceutical compositions comprising a compound of Formula Ior an enantiomer or pharmaceutically acceptable salt thereof, incombination with a second therapeutic agent.

This invention also provides compounds of Formula I and enantiomers andpharmaceutically acceptable salts thereof for use as medicaments in thetreatment of AKT protein kinase-mediated conditions.

An additional aspect of the invention is the use of a compound ofFormula I, or an enantiomer or pharmaceutically acceptable salt thereof,for therapy. In one embodiment, the therapy comprises the treatment ofan AKT protein kinase-mediated condition.

This invention further provides kits for the treatment of an AKT proteinkinase-mediated disease or disorder, said kit comprising a compound ofFormula I, or an enantiomer or pharmaceutically acceptable salt thereof,a container, and optionally a package insert or label indicating atreatment. The kits may further comprise a second compound orformulation comprising a second pharmaceutical agent useful for treatingsaid disease or disorder.

This invention further includes methods of preparing, methods ofseparating, and methods of purifying of the compounds of this invention.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification, or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature and similar materials differs from or contradicts thisapplication, including but not limited to defined terms, term usage,described techniques, or the like, this application controls.

DEFINITIONS

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Examples ofalkyl groups include, but are not limited to, methyl (“Me”, —CH₃), ethyl(“Et”, —CH₂CH₃), 1-propyl (“n-Pr”, n-propyl, —CH₂CH₂CH₃), 2-propyl(“i-Pr”, i-propyl, —CH(CH₃)₂), 1-butyl (“n-Bu”, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (“i-Bu”, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (“s-Bu”,s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (“t-Bu”, t-butyl,tert-butyl, —C(CH₃)₃), 2,2-dimethylpropyl (CH₂C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The terms “cycloalkyl,” “carbocycle,” “carbocyclyl” and “carbocyclicring” as used herein are used interchangeably and refer to saturated orpartially unsaturated cyclic hydrocarbon radical having from three totwelve carbon atoms. The term “cycloalkyl” includes monocyclic andpolycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, whereinthe polycyclic structures optionally include a saturated or partiallyunsaturated cycloalkyl ring fused to a saturated, partially unsaturatedor aromatic cycloalkyl or heterocyclic ring. The cycloalkyl may beoptionally substituted independently with one or more substituentsdescribed herein.

Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” as usedherein are used interchangeably and refer to a saturated or partiallyunsaturated carbocyclic radical of 3 to 8 ring atoms in which at leastone ring atom is a heteroatom independently selected from nitrogen,oxygen and sulfur, the remaining ring atoms being C, where one or morering atoms may be optionally substituted independently with one or moresubstituents described below. The radical may be a carbon radical orheteroatom radical. The term “heterocycle” includes heterocycloalkoxy.“Heterocyclyl” also includes radicals where heterocycle radicals arefused with a saturated, partially unsaturated, or aromatic carbocyclicor heterocyclic ring. The heterocycle may be C-attached or N-attachedwhere such is possible. For instance, a group derived from pyrrole maybe pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, agroup derived from imidazole may be imidazol-1-yl (N-attached) orimidazol-3-yl (C-attached). Examples of heterocyclic groups wherein 2ring carbon atoms are substituted with oxo (═O) moieties areisoindoline-1,3-dionyl and 1,1-dioxo-thiomorpholinyl. The heterocyclegroups herein are optionally substituted independently with one or moresubstituents described herein.

Exemplary heterocyclyl groups include, but are not limited to, oxiranyl,aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl,1,3-dithietanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl.

The term “heteroaryl” as used herein refers to a monovalent aromaticradical of a 5-, 6-, or 7-membered ring and includes fused ring systems(at least one of which is aromatic) of 5-10 atoms containing at leastone heteroatom independently selected from nitrogen, oxygen, and sulfur.The heteroaryl may be C-attached or N-attached where such is possible.Heteroaryl groups may be optionally substituted independently with oneor more substituents described herein.

Examples of heteroaryl groups include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

The term “halogen” as used herein means fluoro, chloro, bromo or iodo.

The term “enantiomer” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another.

The term “diastereomer” refers to a pair of optical isomers which arenot mirror images of one another.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The phrase “effective amount” means an amount of compound that, whenadministered to a mammal in need of such treatment, is sufficient to (i)treat or prevent a particular disease, condition, or disorder mediatedby the activity of one or more AKT protein kinases, tyrosine kinases,additional serine/threonine kinases, and/or dual specificity kinases,(ii) attenuate, ameliorate, or eliminate one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevent or delaythe onset of one or more symptoms of the particular disease, condition,or disorder described herein.

“Treating” is intended to mean at least the mitigation of a diseasecondition in a mammal, such as a human, that is affected, at least inpart, by the activity of one or more AKT protein kinases, tyrosinekinases, additional serine/threonine kinases, and/or dual specificitykinases. The terms “treat” and “treatment” refer to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to prevent or slow down (lessen) an undesired physiological change ordisorder. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder as well as those found to be predisposed to havingthe disease condition but have not yet been diagnosed as having it;modulating and/or inhibiting the disease condition. The terms“treating”, “treat”, or “treatment” embrace both preventative, i.e.,prophylactic, and palliative treatment.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “a” as used herein means one or more.

As used herein, the terms “compound of this invention,” “compounds ofthe present invention” and “compounds of Formula I” includes compoundsof Formula I and tautomers, resolved enantiomers, resolveddiastereomers, racemic mixtures, solvates, metabolites, salts (includingpharmaceutically acceptable salts) and pharmaceutically acceptableprodrugs thereof.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, an arylalkyl radical is attached to the structure inquestion by the alkyl group.

AKT Inhibitors

The inventive compounds of Formula I are useful for inhibiting AKTprotein kinases. The compounds of Formula I may also be useful asinhibitors of tyrosine kinases as well as serine and threonine kinasesin addition to AKT. Such compounds have utility as therapeutic agentsfor diseases that can be treated by the inhibition of the AKT proteinkinase signaling pathway and tyrosine and serine/threonine kinasereceptor pathways.

In general, the invention includes compounds of the Formula I:

and resolved enantiomers, resolved diastereomers, and pharmaceuticallyacceptable salts thereof, wherein:

R¹ and R^(1a) are independently selected from H, Me, Et, vinyl, CF₃,CHF₂ or CH₂F;

R² is H, OH, OMe or F;

R^(2a) is H, Me or F;

R³ is H, Me, Et, or CF₃;

A is

G is phenyl optionally substituted by one to four R^(e) groups or a 5-6membered heteroaryl optionally substituted by a halogen;

R⁵ and R⁶ are independently H, OCH₃, C₃-C₆-cycloalkyl optionallysubstituted with F, OH, C₁-C₃ alkyl or O(C₁-C₃ alkyl), 4-6 memberedheterocycle optionally substituted with F, OH, C₁-C₃ alkyl,cyclopropylmethyl or C(═O)(C₁-C₃ alkyl), or C₁-C₆-alkyl optionallysubstituted with one or more groups independently selected from OH, oxo,O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂,cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, oxetanyl or tetrahydropyranyl,

or R⁵ and R⁶ together with the nitrogen to which they are attached forma 4-7 membered heterocyclic ring optionally substituted with one or moregroups independently selected from OH, halogen, oxo, CF₃, CH₂CF₃,CH₂CH₂OH, O(C₁-C₃ alkyl), C(═O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃,cyclopropylmethyl and C₁-C₃ alkyl, or

R^(c) is hydrogen and R^(d) and R⁶ together with the atoms to which theyare attached form a 4 to 6 membered heterocyclic ring having onenitrogen atom;

R^(a) and R^(b) are H,

or R^(a) is H, and R^(b) and R⁶ together with the atoms to which theyare attached form a 5-6 membered heterocyclic ring having one or tworing nitrogen atoms;

R^(c) and R^(d) are H or Me,

or R^(c) and R^(d) together with the atom to which they are attachedfrom a cyclopropyl ring;

each R^(e) is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,O—(C₁-C₆-alkyl), CF₃, OCF₃, S(C₁-C₆-alkyl), CN, OCH₂-phenyl, NH₂, NO₂,NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂,OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), andC(O)N(C₁-C₆-alkyl)₂;

m and n are independently 0, 1, 2 or 3 with the proviso that (m+n) mustequal 2, 3 or 4; and

p is 0 or 1.

In general, the invention includes compounds of the Formula I:

and resolved enantiomers, resolved diastereomers, and pharmaceuticallyacceptable salts thereof, wherein:

R¹ and R^(1a) are independently selected from H, Me, Et, vinyl, CF₃,CHF₂ or CH₂F;

R² is H, OH, OMe or F;

R^(2a) is H, Me or F;

R³ is H, Me, Et, or CF₃;

A is

G is phenyl optionally substituted by one to four R^(e) groups or a 5-6membered heteroaryl optionally substituted by a halogen;

R⁵ and R⁶ are independently H, OCH₃, C₃-C₆-cycloalkyl optionallysubstituted with F, OH, C₁-C₃ alkyl or O(C₁-C₃ alkyl), 4-6 memberedheterocycle optionally substituted with F, OH, C₁-C₃ alkyl,cyclopropylmethyl or C(═O)(C₁-C₃ alkyl), or C₁-C₆-alkyl optionallysubstituted with one or more groups independently selected from OH, oxo,O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂,cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, oxetanyl or tetrahydropyranyl,

or R⁵ and R⁶ together with the nitrogen to which they are attached forma 4-7 membered heterocyclic ring optionally substituted with one or moregroups independently selected from OH, halogen, oxo, CF₃, CH₂CF₃,CH₂CH₂OH, O(C₁-C₃ alkyl), C(═O)CH₃, NHMe, N(Me)₂, S(O)₂CH₃,cyclopropylmethyl and C₁-C₃ alkyl;

R^(a) and R^(b) are H,

or R^(a) is H, and R^(b) and R⁶ together with the atoms to which theyare attached form a 5-6 membered heterocyclic ring having one or tworing nitrogen atoms;

R^(c) and R^(d) are H or Me,

or R^(c) and R^(d) together with the atom to which they are attachedfrom a cyclopropyl ring;

each R^(c) is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,O—(C₁-C₆-alkyl), CF₃, OCF₃, S(C₁-C₆-alkyl), CN, OCH₂-phenyl, NH₂, NO₂,NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂,OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), andC(O)N(C₁-C₆-alkyl)₂;

m and n are independently 0, 1 or 2, with the proviso that (m+n) mustequal 2, 3 or 4; and

p is 0 or 1.

Referring to the G group of Formula I, examples include phenyl (“Ph”)optionally substituted with one or more R^(e) groups independentlyselected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl,cyclopropyl, CN, CF₃, OMe, OEt, OCF₃, NO₂, SMe and OCH₂Ph. Exemplaryembodiments of G include phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl,4-ethylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl,4-cyanophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-thiomethylphenyl,4-trifluoromethoxyphenyl, 4-cyclopropylphenyl, 4-chloro-3-fluorophenyl,3,4-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl,4-cyano-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl,3,5-dichlorophenyl. 3,5-difluorophenyl, 3-chloro-5-fluorophenyl,3-chloro-4-fluorophenyl, 3-bromo-4-fluorophenyl,3,5-difluoro-4-chlorophenyl, 2,3-difluoro-4-chlorophenyl,2,5-difluoro-4-chlorophenyl, 3,5-difluoro-4-bromophenyl,2,3-difluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl,4-(OCH₂Ph)-phenyl, 4-chlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-bromophenyl, 4-fluorophenyl, 3,4-difluorophenyl,2,4-difluorophenyl 4-bromophenyl, 4-chloro-2-fluorophenyl,4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl,4-iodophenyl, 4-nitrophenyl, 4-tert-butylphenyl, 2-fluorophenyl,3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl,3-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-trifluoromethylphenyl and4-tri fluoromethoxyphenyl.

Referring to the G group of Formula I, the phrase “5-6 memberedheteroaryl optionally substituted by a halogen” includes thiophenes andpyridines, optionally substituted by halogens. Particular examplesinclude, but are not limited to, the structures:

In one embodiment of Formula I, R³ is H.

In another embodiment of Formula I, R³ is methyl, wherein said methyl isoptionally in the (S) configuration.

In another embodiment of Formula I, R³ is ethyl.

In one embodiment of Formula I, R¹ is methyl, wherein said methyl isoptionally in the (R) configuration. In certain embodiments of FormulaI, R^(1a) is H. In certain embodiments of Formula I, R¹ and R^(1a) areboth methyl.

In another embodiment of Formula I, R¹ is H. In certain embodiments ofFormula I, R^(1a) is H.

In another embodiment of Formula I, R¹ is ethyl. In certain embodimentsof Formula I, R^(1a) is H.

In another embodiment of Formula I, R¹ is CH═CH₂ (vinyl). In certainembodiments of Formula I, R^(1a) is H.

In another embodiment of Formula I, R¹ is CH₂OH. In certain embodimentsof Formula I, R^(1a) is H.

In one embodiment of Formula I, R^(1a) is H.

In one embodiment of Formula I, R² and R^(2a) are H.

In another embodiment of Formula I, R² and R^(2a) are F.

In another embodiment of Formula I, R² is F and R^(2a) is H.

In another embodiment of Formula I, R² is OH. In certain embodiments ofFormula I, R^(2a) is H.

In another embodiment of Formula I, R² is OMe.

In one embodiment of Formula I, G is phenyl optionally substituted withone to four R^(e) groups.

In one embodiment of Formula I, G is phenyl optionally substituted withone to four groups independently selected from F, Cl, Br, I, methyl,ethyl, isopropyl, tert-butyl, cyclopropyl, CN, CF₃, OMe, OEt, OCF₃, NO₂,SMe and OCH₂Ph. Exemplary embodiments of G include phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl,4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl,4-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-ethoxyphenyl,4-thiomethylphenyl, 4-trifluoromethoxyphenyl, 4-cyclopropylphenyl,4-chloro-3-fluorophenyl, 3,4-difluorophenyl, 4-bromo-3-fluorophenyl,3-fluoro-4-methylphenyl, 3-fluoro-4-methoxyphenyl,3-fluoro-4-trifluoromethylphenyl, 4-cyano-3-fluorophenyl,3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 3,5-dichlorophenyl.3,5-difluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl,3-bromo-4-fluorophenyl, 3,5-difluoro-4-chlorophenyl,2,3-difluoro-4-chlorophenyl, 2,5-difluoro-4-chlorophenyl,3,5-difluoro-4-bromophenyl, 2,3-difluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 4-(OCH₂Ph)-phenyl, 4-chlorophenyl,2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-bromophenyl, 4-fluorophenyl,3,4-difluorophenyl, 2,4-difluorophenyl 4-bromophenyl,4-chloro-2-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl,4-trifluoromethylphenyl, 4-iodophenyl, 4-nitrophenyl,4-tert-butylphenyl, 2-fluorophenyl, 3-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl,3-fluoro-4-trifluoromethylphenyl and 4-trifluoromethoxyphenyl.

In one embodiment of Formula I, G is 4-chlorophenyl, 4-fluorophenyl,4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl,4-trifluormethoxyphenyl, 4-thiomethylphenyl, 3-fluoro-4-chlorophenyl,2,4-dichlorophenyl or 3,4-dichlorophenyl.

In one embodiment of Formula I, G may be a 5-6 membered monocyclicheteroaryl optionally substituted by one or more halogens. In certainembodiments, G may be a thiophene or a pyridine, optionally substitutedby one or more halogens. In certain embodiments, G is substituted by onehalogen. Particular embodiments include:

In one embodiment of Formula I, R⁵ is H or ethyl.

In one embodiment of Formula I, R⁶ is H or ethyl.

In one embodiment of Formula I, R⁶ is hydrogen, ethyl or isopropyl.

In one embodiment of Formula I, R^(a) and R^(b) are H.

In one embodiment of Formula I, R^(c) and R^(d) are H.

In one embodiment, R^(c) is hydrogen and R^(d) and R⁶ together with theatoms to which they are attached form a 4 to 6 membered heterocyclicring having one nitrogen atom. In certain embodiments, m is 0, R^(c) ishydrogen, and R^(d) and R⁶ together with the atoms to which they areattached form a 4 to 6 membered heterocyclic ring having one nitrogenatom, such that A has the formula:

wherein q is 1 or 2 and n is 1 or 2. In certain embodiments, n is 1 andq is 1, n is 1 and q is 2, or n is 2 and q is 2.

In one embodiment of Formula I, m and n are independently 0, 1 or 2,with the proviso that (m+n) must equal 2, 3 or 4. In particularembodiments, m is 0 and n is 2, m is 1 and n is 2, m is 2 and n is 2, mis 1 and n is 1, m is 2 and n is 1, or m is 2 and n is 0.

In one embodiment of Formula I, m and n are both 1.

In another embodiment of Formula I, m is 2 and n is 0. In anotherembodiment of Formula I, n is 2 and m is 0.

In one embodiment of Formula I, m is 1, n is 1, p is 0, such that A isrepresented by the Formula 1:

wherein G, R⁵, R⁶, R^(c) and R^(d) are as defined herein.

In certain embodiments of Formula 1, R^(c) and R^(d) are H.

In certain embodiment of Formula 1, R⁵ is H or ethyl.

In certain embodiment of Formula 1, R⁶ is H or ethyl.

In certain embodiments of Formula I, m is 1, n is 1 and p is 1, suchthat A is represented by the Formula 2:

wherein G, R⁶, R⁷, and R⁸ are as defined herein.

In certain embodiments of Formula 2, R^(a) and R^(b) are H.

In certain embodiments of Formula 2, R^(c) and R^(d) are H.

In certain embodiment of Formula 2, R⁵ is H or ethyl.

In certain embodiment of Formula 2, R⁶ is H or ethyl.

In particular embodiments, A is:

In additional embodiments, A is selected from the structures:

In additional embodiments, A is:

In particular embodiments, A is selected from:

In particular embodiments, A is:

In certain embodiments, the salt is a “pharmaceutically acceptable salt”which, unless otherwise indicated, includes salts that retain thebiological effectiveness of the corresponding free acid or base of thespecified compound and are not biologically or otherwise undesirable.

The compounds of Formula I also include other salts of such compoundswhich are not necessarily pharmaceutically acceptable salts, and whichmay be useful as intermediates for preparing and/or purifying compoundsof Formula I and/or for separating enantiomers of compounds of FormulaI.

Synthesis of Compounds of Formula I

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Sigma-Aldrich (St. Louis, Mo.), Alfa Aesar (Ward Hill,Mass.), or TCI (Portland, Oreg.), or are readily prepared using methodswell known to those skilled in the art (e.g., prepared by methodsgenerally described in Louis F. Fieser and Mary Fieser, Reagents forOrganic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), or BeilsteinsHandbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin,including supplements (also available via the Beilstein onlinedatabase).

For illustrative purposes, Schemes 1 to 8 show general methods forpreparing the compounds of the present invention, as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a method of preparing compound 9 of Formula I, wherein pis 1; R^(a) and R^(b) are H; R², R^(2a), R¹, R^(1a), R³, R⁵, R⁶, R^(c),R^(d), m and n are defined herein; and Pg and Pg′ are amine protectinggroups with mutually exclusive removal conditions (e.g. Pg=Boc andPg′=Cbz—see, for example, ‘Protective Groups in Organic Synthesis’ byGreene and Wuts, Wiley-Interscience, third edition, Chapter 7).Reductive amination of the amine 2 onto the aldehyde 1 using standardconditions, such as NaBH(OAc₃)/AcOH at 0° C. to 50° C. gives thesubstituted amine 3. Acylation of this substituted amine 3 with thesubstituted acylpiperazine 4 in the presence of a base (such as Hunig'sbase) at −20° C. to 100° C. gives the protected piperazine 5. Removal ofthis protecting group (e.g. for a Cbz group, hydrogenolysis, etc.) givesthe piperazine 6. Treatment of this piperazine 6 with the halogenatedpyrimidine 7 at 25° C. to 250° C. and/or at high pressure and/ormicrowave assistance gives the intermediate 8. Deprotection of theamine, (for example, for a Boc group, using HCl in dioxane at 0° C. to50° C.) and final optional functionalization of the amine (e.g.alkylation, reductive amination or acylation under standard conditionsto introduce new substituents) gives rise to the final compounds 9. Ifneed be, these analogues may then be subject to separation techniques togive the single enantiomers.

Scheme 2 shows a method of preparing compound 20 of Formula I, whereinR¹, R² and R^(2a) are hydrogen; R^(1a) is Me; and R³, R⁵, R⁶, R^(a),R^(b), R^(c), R^(d), m, n and p are as defined herein. According toScheme 2, bromination of (+)-pulegone 10 with bromine gives thedibromide 11. The treatment of the dibromide 11 with a base, such assodium ethoxide, provides the pulegenate 12. Oxidative cleavage of thepulegenate 12 using, for example, ozonolysis at low temperature followedby reductive workup (e.g. Zn) or NaIO₄/OsO₄ at 5° C. to 50° C.) givesthe keto ester 13. Treatment of the keto ester 13 with thiourea in thepresence of a base, such as KOH in ethanol, followed by reduction of themercapto group under standard conditions (e.g. Raney Ni catalyst inammonia) affords the hydroxypyrimidine 16. Activation of compound 16(e.g. halogenation) using, for example, POCl₃ or SOCl₂ at −20° C. to100° C. to give the chloropyrimidine, gives the functionalizedpyrimidine-cyclopentane unit 17. Displacement of the leaving group,using a suitable protected/substituted piperidine 18 at 0° C. to 150° C.gives the piperidine 19. Deprotection of the amine, (for example, for aBoc group, using HCl in dioxane at 0° C. to 50° C.) and final optionalfunctionalization of the amine (e.g. alkylation, reductive amination oracylation to introduce new substituents) gives rise to the finalcompound 20. If need be, these analogues may then be subject toseparation techniques to give the single enantiomers.

Scheme 3 shows a method of preparing compound 29 of Formula I, whereinR² is OH, R^(2a) is H and R¹, R^(1a), R³, R⁵, R⁶, R⁷, R^(a), R^(b),R^(c), R^(d), m, n and p are defined herein. According to Scheme 3,treatment of the keto ester 21 with thiourea in the presence of a basesuch as KOH in ethanol, followed by reduction of the mercapto groupunder standard conditions (e.g. Raney Ni catalyst in ammonia) affordsthe hydroxypyrimidine 23. Activation (e.g. halogentation) of thehydroxypyrimidine 23 under standard conditions (e.g., POCl₃) providesthe 4-halopyrimidine 24. The oxidation of the 4-chloropyrimidine 24 withan oxidizing agent, such as m-CPBA, or hydrogen peroxide provides theN-oxide 25. Rearrangement of the N-oxide 25 with acetic anhydride yieldsthe intermediate 26. Compound 26 is then hydrolyzed (e.g. LiOH or NaOHat 0° C. to 50° C.) to give the alcohol 27. Compound 27 is then reactedwith the desired substituted piperazine 18 according to the proceduredescribed in Scheme 1 to provide compound 28. If compound 29 is toundergo optional functionalization, the alcohol 28 may be protected(e.g. TBS group) at this stage to avoid potential complications. Removalof the protecting group (Pg) of compound 28, for example using acid(e.g. TFA at −20° C. to 50° C.) for a Boc group and subsequent, optionalfunctionalization of the free amine (e.g. alkylation, acylation,reductive amination, etc.) under standard conditions gives the fullyfunctionalized compound 29. This compound 29 may also be subject toseparation techniques to provide the single diastereomers by eitherchiral separation, standard non-chiral separation (e.g. columnchromatography, HPLC, SFC, etc), recrystallization or derivitizationtechniques.

Scheme 4 shows an alternative method of preparing compound 32 of FormulaI, wherein R² and R^(2a) are H and R¹, R^(1a), R³, R⁵, R⁶, R⁷, R^(a),R^(b), R^(c), R^(d), m, n and p are defined herein. According to Scheme3, amination of keto ester 21 using an ammonia synthon gives compound30. Pyrimidine formation using, for example, ammonium formate, in thepresence of formamide at 50° C. to 250° C. and/or at high pressureand/or microwave assistance gives the bicyclic unit 23. Activation ofcompound 23 using, for example, POCl₃ or SOCl₂, gives the activatedpyrimidine and displacement of this leaving group, using a suitableprotected/substituted piperidine 18 at 0° C. to 150° C. gives thepiperidine 31. Deprotection of the amine, (for example, for a Boc group,using HCl in dioxane at 0° C. to 50° C.) and final optionalfunctionalization of the amine (e.g. alkylation, reductive amination oracylation to introduce new substituents) gives rise to the finalcompounds 32. If need be, these analogues may then be subject toseparation techniques to give the single enantiomers.

Scheme 5 shows a method of preparing compound 35 of Formula I, whereinR² is fluorine, R^(2a) is hydrogen and R¹, R^(1a), R³, R⁵, R⁶, R⁷,R^(a), R^(b), R^(c), R^(d), m, n and p are defined herein. According toScheme 5, treatment of the alcohol 33 with a fluorinating agent, such asDAST at −78° C. to 100° C., gives the fluoro derivative 34. Deprotectionof the amine, (for example, for a Boc group, using HCl in dioxane at 0°C. to 50° C.) and final optional functionalization of the amine (e.g.alkylation, reductive amination or acylation to introduce newsubstituents) gives rise to the final compound 35. If need be, theseanalogues may then be subject to separation techniques to give thesingle enantiomers.

Scheme 6 shows a method of preparing compound 39 of Formula I, wherein pis 0; NR⁵R⁶ is such that the amine cannot be further acylated bycompound 4; and R², R^(2a), R¹, R^(1a), R³, R⁵, R⁶, R⁷, Ra, Rb, Rc, Rd,m and n are defined herein. Acylation of the substituted amine 36 withthe substituted acylpiperazine 4 in the presence of a base (such asHunig's base) at −20° C. to 100° C. gives the protected piperazine 37(Pg=protecting group). Removal of this protecting group (e.g. for a Bocgroup, HCl in dioxane, or for a Cbz group, hydrogenation, etc.) givesthe piperazine 38. Treatment of this piperazine 38 with the halogenatedpyrimidine 7 at 50° C. to 250° C. and/or at high pressure and/ormicrowave assistance gives the product 39. If need be, these analoguesmay then be subject to separation techniques to give the singleenantiomers.

Scheme 7 demonstrates an alternative way for the formation of (44) ofFormula I, wherein R², R^(2a), R¹, R^(1a), R³, R⁵, R⁶, R⁷, Ra, Rb, Rc,Rd, m, p and n are defined herein and Pg and Pg¹ are protecting groupswith mutually exclusive removal conditions (e.g. Boc and Cbz groups).Acylation of the substituted amine 40 with the substitutedacylpiperazine 4 in the presence of a base (such as Hunig's base) at−20° C. to 100° C. gives the protected piperazine 41 (Pg=protectinggroup). Removal of this protecting group (e.g. for a Boc group, HCl indioxane, or for a Cbz group, hydrogenation, etc.) gives the piperazine42. Treatment of this piperazine 42 with the halogenated pyrimidine 7 at50° C. to 250° C. and/or at high pressure and/or microwave assistancegives the intermediate 43. Removal of the amine protecting group (e.g.for a Boc, HCl in dioxane, at 0° C. to 50° C., etc.) and subsequentoptional functionalization (e.g. alkylation, reductive amination oracylation to introduce new substituents) gives rise to the finalcompound 44. If need be, these analogues may then be subject toseparation techniques to give the single enantiomers.

Scheme 8 shows an alternative way in which compound 29 of Formula I,wherein R² is OH; R^(2a) is H; R¹, R^(1a), R³, R⁵, R⁶, R⁷, R^(a), R^(b),R^(c), R^(d), m, p and n are defined herein; and Pg and Pg′ areprotecting groups with mutually exclusive removal conditions (e.g. Bocand TBS groups—see, for example, ‘Protective Groups in OrganicSynthesis’ by Greene and Wuts, Wiley-Interscience) may be prepared.According to Scheme 8, compound 45 is reacted with the desiredsubstituted piperazine 46 according to the procedure described in Scheme1 to provide compound 47. Protection of this alcohol 47 (e.g. TBS group,using TBSOTf in the presence of an amine base, such as Hunig's base)gives compound 48. Removal of the amine protecting group [for exampleusing acid (e.g. TFA at −20° C. to 50° C.) for a Boc group] gives thefree amine 49. Treatment of compound 49 with a phosgene equivalent (suchas triphosgene) gives the activated intermediate 50, and subsequenttreatment with the amine 51 in the presence of a base (e.g. Hunig's baseat −50° C. to 100° C.) gives the urea 52. Removal of the newlyintroduced amine protecting group (Pg) in compound 52 using conditionsknown not to affect the hydroxyl protecting group (Pg′) (e.g. TFA at−50° C. to 30° C. for a Boc group) and subsequent optionalfunctionalization of the free amine (e.g. alkylation, acylation,reductive amination, etc.) under standard conditions gives the fullyfunctionalized compound 53. Finally, removal of the alcohol protectinggroup (e.g. a fluoride source such as TBAF for a TBS group at −50° C. to+50° C.) gives the final compound 54. This compound 54 may also besubject to separation techniques to provide the single diastereomers byeither chiral separation, standard non-chiral separation (e.g. columnchromatography, HPLC, SFC, etc), recrystallization or derivitizationtechniques.

Similar procedures can also be envisaged (without the alcoholprotection/deprotection steps) for compounds where R² is H or F insteadof OH.

Accordingly, another aspect of the invention provides a method ofpreparing compounds of Formula I, comprising:

(a) reacting a compound having the formula:

wherein R¹, R^(1a), R² and R^(2a) are as defined herein and Hal is ahalogen, with a compound of the formula:

wherein G, R³, R^(c), R^(d), n, m and p are as defined herein and Pg isa protecting group as defined herein, followed by deprotection andoptional functionalization to prepare a compound of Formula I;

(b) activation of a compound of formula:

wherein R¹ and R^(1a) are as defined herein, with POCl₃ or SOCl₂,followed by displacement with a compound of formula:

wherein G, R³, R^(c), R^(d), n and m are as defined herein and Pg is aprotecting group as defined herein, followed by deprotection andoptional functionalization to prepare a compound of Formula I; or

(c) reacting a compound of formula:

wherein R¹, R^(1a) and R³ are as defined herein and Pg′ is a protectivegroup as defined herein, with a compound of formula:

wherein G, R^(a), R^(b), R^(c), R^(d), n, m and p are as defined hereinand Pg is a protecting group as defined herein, followed by deprotectionand optional functionalization to prepare a compound of Formula I.

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Methods of Separation

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers anddiastereomers, and mixtures, racemic or otherwise, thereof. Accordingly,this invention also includes all such isomers, including diastereomericmixtures, pure diastereomers and pure enantiomers of the compounds ofthis invention. Diastereomers have different physical properties, e.g.,melting points, boiling points, spectral properties, and reactivities.

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (SMB) and preparative thin or thick layer chromatography, aswell as techniques of small scale thin layer and flash chromatography.One skilled in the art will apply techniques most likely to achieve thedesired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.,(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111).

By method (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (“Chiral LiquidChromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York;Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

The compounds of the present invention may also exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention. For example, proton tautomers (also known as prototropictautomers) include interconversions via migration of a proton, such asketo-enol and imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

Administration and Pharmaceutical Formulations

The compounds of the invention may be administered by any convenientroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),vaginal, intraperitoneal, intrapulmonary and intranasal.

The compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches, etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, (8^(th) Ed. 2004); Alfonso R. Gennaro et al.,Remington: The Science and Practice of Pharmacy, (20^(th) Ed. 2000); andRaymond C. Rowe, Handbook of Pharmaceutical Excipients, (5^(th) Ed.2005). The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents, diluents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

One embodiment of the present invention includes a pharmaceuticalcomposition comprising a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof. In a further embodiment, thepresent invention provides a pharmaceutical composition comprising acompound of Formula I, or a stereoisomer or pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier orexcipient.

Methods of Treatment with Compounds of Formula I

The compounds of the present invention can be used as prophylactics ortherapeutic agents for treating diseases or disorders mediated bymodulation or regulation of AKT protein kinases, tyrosine kinases,additional serine/threonine kinases, and/or dual specificity kinases.AKT protein kinase mediated conditions that can be treated according tothe methods of this invention include, but are not limited to,inflammatory, hyperproliferative cardiovascular, neurodegenerative,gynecological, and dermatological diseases and disorders.

In one embodiment, said pharmaceutical composition is for the treatmentof hyperproliferative disorders, including cancers of the followingcategories: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; (2) Lung: bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small celllung, small cell lung; (3) Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); (4) Genitourinary tract: kidney (adenocarcinoma, Wilm'stumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); (5) Liver: hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma,osteoid osteoma and giant cell tumors; (7) Nervous system: skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastomamultifonn. oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8)Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (9)Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin:advanced melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, keloids, psoriasis; (11) Adrenal glands:neuroblastoma; (12) Breast: metastatic breast; breast adenocarcinoma;(13) Colon; (14) Oral cavity; (15) Hairy cell leukemia; (16) Head andneck; (17) and others including refractory metastatic disease; Kaposi'ssarcoma; Bannayan-Zonana syndrome; and Cowden disease orLhermitte-Duclos disease, among other kinds of hyperproliferativedisorders.

Compounds and methods of this invention can be also used to treatdiseases and conditions such as rheumatoid arthritis, osteoarthritis,Chron's disease, angiofibroma, ocular diseases (e.g., retinalvascularisation, diabetic retinopathy, age-related macular degeneration,macular degeneration, etc.), multiple sclerosis, obesity, restenosis,autoimmune diseases, allergy, asthma, endometriosis, atherosclerosis,vein graft stenosis, peri-anastomatic prothetic graft stenosis, prostatehyperplasia, chronic obstructive pulmonary disease, psoriasis,inhibition of neurological damage due to tissue repair, scar tissueformation (and can aid in wound healing), multiple sclerosis,inflammatory bowel disease, infections, particularly bacterial, viral,retroviral or parasitic infections (by increasing apoptosis), pulmonarydisease, neoplasm, Parkinson's disease, transplant rejection (as animmunosupressant), septic shock, etc.

Accordingly, another aspect of this invention provides a method oftreating diseases or medical conditions in a mammal mediated by AKTprotein kinases, comprising administering to said mammal one or morecompounds of Formula I or a pharmaceutically acceptable salt or prodrugthereof in an amount effective to treat or prevent said disorder.

In the case of cancer, an effective amount of the drug may reduce thenumber of cancer cells; reduce the tumor size; inhibit (i.e., slow tosome extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and/or kill existingcancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy,efficacy can be measured, for example, by assessing the time to diseaseprogression (TTP) and/or determining the response rate (RR).

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

This invention also provides compounds of Formula I for use in thetreatment of AKT protein kinase-mediated conditions.

An additional aspect of the invention is the use of a compound ofFormula I in the preparation of a medicament for therapy, such as forthe treatment or prevention of AKT protein kinase-mediated conditions.

Combination Therapy

The compounds of this invention and stereoisomers and pharmaceuticallyacceptable salts thereof may be employed alone or in combination withother therapeutic agents for treatment. The compounds of the presentinvention can be used in combination with one or more additional drugs,for example an anti-inflammatory compound that works by a differentmechanism of action. The second compound of the pharmaceuticalcombination formulation or dosing regimen preferably has complementaryactivities to the compound of this invention such that they do notadversely affect each other. Such molecules are suitably present incombination in amounts that are effective for the purpose intended. Thecompounds may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time.

Examples of chemotherapeutic agents include Erlotinib (TARCEVA®,Genentech, Inc./OSI Pharm.), Trastuzumab (HERCEPTIN®, Genentech, Inc.);bevacizumab (AVASTIN®, Genentech, Inc.); Rituximab (RITUXAN®, Genentech,Inc./Biogen Idec, Inc.), Bortezomib (VELCADE®, Millennium Pharm.),Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer),Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis),PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU(5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth),Lapatinib (GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336),Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®,AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such asthiotepa and CYTOXAN® cyclosphosphamide, ADRIAMYCIN® (doxorubicin),TAXOL® (paclitaxel; Bristol-Myers Squibb, Princeton, N.J.), ABRAXANE®(Cremophor-free), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony,France).

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the disordersdescribed above is provided. In one embodiment, the kit comprises acontainer comprising a compound of this invention. Suitable containersinclude, for example, bottles, vials, syringes, blister pack, etc. Thecontainer may be formed from a variety of materials such as glass orplastic. The container may hold a compound of this invention or aformulation thereof which is effective for treating the condition andmay have a sterile access port (for example, the container may be anintravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle).

The kit may further comprise a label or package insert on or associatedwith the container. In one embodiment, the label or package insertsindicates that the composition comprising a compound of this inventioncan be used to treat a disorder mediated, for example, by AKT kinase.The label or package insert may also indicate that the composition canbe used to treat other disorders.

In certain embodiments, the kits are suitable for the delivery of solidoral forms of a compound of this invention, such as tablets or capsules.Such a kit preferably includes a number of unit dosages. Such kits caninclude a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to another embodiment, a kit may comprise (a) a firstcontainer with a compound of this invention contained therein; and (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound useful for treating a disorder mediated by AKT kinase.Alternatively, or additionally, the kit may further comprise a thirdcontainer comprising a pharmaceutically-acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of this invention and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of this invention and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In certain other embodiments wherein the kit comprises a composition ofthis invention and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. In certainembodiments, the kit comprises directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

Accordingly, a further aspect of this invention provides a kit fortreating a disorder or disease mediated by Akt kinase, wherein said kitcomprises a) a first pharmaceutical composition comprising a compound ofthis invention or a pharmaceutically acceptable salt thereof; and b)instructions for use.

In certain embodiments, the kit further comprises (c) a secondpharmaceutical composition, wherein the second pharmaceuticalcomposition comprises a second compound suitable for treating a disorderor disease mediated by Akt kinase. In certain embodiment comprising asecond pharmaceutical composition, the kit further comprisesinstructions for the simultaneous, sequential or separate administrationof said first and second pharmaceutical compositions to a patient inneed thereof. In certain embodiments, said first and secondpharmaceutical compositions are contained in separate containers. Inother embodiments, said first and second pharmaceutical compositions arecontained in the same container.

Although the compounds of Formula I are primarily of value astherapeutic agents for use in mammals, they are also useful whenever itis required to control AKT protein kinases, tyrosine kinases, additionalserine/threonine kinases, and/or dual specificity kinases. Thus, theyare useful as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.

The activity of the compounds of this invention may be assayed for AKTprotein kinases, tyrosine kinases, additional serine/threonine kinases,and/or dual specificity kinases in vitro, in vivo, or in a cell line. Invitro assays include assays that determine inhibition of the kinaseactivity. Alternate in vitro assays quantitate the ability of theinhibitor to bind to kinases and may be measured either byradiolabelling the inhibitor prior to binding, isolating theinhibitor/kinase complex and determining the amount of radiolabel bound,or by running a competition experiment where new inhibitors areincubated with known radioligands. These and other useful in vitro andcell culture assays are well known to those of skill in the art.

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as hereinafter claimed.

BIOLOGICAL EXAMPLES AKT-1 Kinase Assay

The activity of the compounds described in the present invention may bedetermined by the following kinase assay, which measures thephosphorylation of a fluorescently-labeled peptide by full-length humanrecombinant active AKT-1 by fluorescent polarization using acommercially available IMAP kit.

The assay materials are obtained from an IMAP AKT Assay Bulk Kit,product #R8059, from Molecular Devices, Sunnyvale, Calif. The kitmaterials include an IMAP Reaction Buffer (5×). The diluted 1×IMAPReaction Buffer contained 10 mM Tris-HCl, pH 7.2, 10 mM MgCl₂, 0.1% BSA,0.05% NaN₃. DTT is routinely added to a final concentration of 1 mMimmediately prior to use. Also included is IMAP Binding Buffer (5×), andIMAP Binding Reagent. The Binding Solution is prepared as a 1:400dilution of IMAP Binding Reagent into 1×IMAP Binding Buffer.

The fluorescein-labeled AKT Substrate (Crosstide) has the sequence(F1)-GRPRTSSFAEG. A stock solution of 20 μM is made up in 1×IMAPReaction Buffer.

The plates used include a Costar 3657 (382-well made of polypropyleneand having a white, v-bottom) that is used for compound dilution and forpreparing the compound-ATP mixture. The assay plate is a PackardProxyPlate™-384 F.

The AKT-1 used is made from full-length, human recombinant AKT-1 that isactivated with PDK1 and MAP kinase 2.

To perform the assay, stock solutions of compounds at 10 mM in DMSO areprepared. The stock solutions and the control compound are seriallydiluted 1:2 nine times into DMSO (10 μL of compound+10 μL of DMSO) togive 50× dilution series over the desired dosing range. Next, 2.1-μLaliquots of the compounds in DMSO are transferred to a Costar 3657 platecontaining 50 μL of 10.4 μM ATP in 1×IMAP Reaction Buffer containing 1mM DTT. After thorough mixing, 2.5-μL aliquots are transferred to aProxyPlate™-384 F plate.

The assay is initiated by the addition of 2.5-μL aliquots of a solutioncontaining 200 nM of fluorescently-labeled peptide substrate and 4 nMAKT-1. The plate is centrifuged for 1 minute at 1000 g and incubated for60 minute at ambient temperature. The reaction is then quenched by theaddition of 15 μL of Binding Solution, centrifuged again and incubatedfor an additional 30 minutes at ambient temperature prior to reading ona Victor 1420 Multilabel HTS Counter configured to measure fluorescencepolarization.

The compounds of Examples 1-20 were tested in the above assay and foundto have an IC₅₀ of less than 1 μM.

PREPARATIVE EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other compounds of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, andwere used without further purification unless otherwise indicated.Tetrahydrofuran (“THF”), dichloromethane (“DCM”), toluene, and dioxanewere purchased from Aldrich in Sure seal bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

¹H NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹H-NMR spectra were obtained as CDCl₃, CD₃OD, D₂O or d₆-DMSOsolutions (reported in ppm), using tetramethylsilane (0.00 ppm) orresidual solvent (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm;d₆-DMSO: 2.50 ppm) as the reference standard. When peak multiplicitiesare reported, the following abbreviations are used: s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

Example 1

(R)—N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide

Step 1:

Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) was added atroom temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol),tert-butyl 2-aminoethylcarbamate (4.5 mL, 28.5 mmol, 1.2 eq.) and aceticacid (2.5 mL) in dichloroethane (20 mL). The reaction mixture wasallowed to stir overnight before being quenched with 0.5M HCl (30 mL).The mixture was then extracted with dichloromethane one time and thenbrine was added. The precipitate was filtered and dried to givetert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%), MS (ESI)m/e (M+H⁺) 285.

Step 2:

Benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol)was added at room temperature to a solution of tert-butyl2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and Hunig'sbase (0.2 mL, 1.2 mmol, 1.5 eq.) in dichloromethane (1.6 mL). Thereaction was allowed to stir overnight. The reaction mixture was thenconcentrated to the crude product, which was purified by flash columnchromatography to afford benzyl4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylateas foam (167 mg, 38%). MS (ESI) m/e (M+H⁺) 531.

Step 3:

A mixture of benzyl4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate(200 mg, 0.38 mmol) in a KOH/MeOH/H₂O (10 mL; prepared as a stocksolution using 10 g KOH, 50 mL MeOH and 25 mL H₂O) solution of wasstirred for 2 hours at 80° C. The reaction was extracted with EtOAc,dried over NaSO₄ and concentrated under reduced pressure to yieldtert-butyl 2-(N-(4-chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate(132 mg, 89%). MS (ESI) m/e (M+H⁺) 397.

Step 4:

(R)-(+)-Pulegone (76.12 g, 0.5 mmol), anhydrous NaHCO₃ (12.5 g) andanhydrous ether (500 mL) were added to a 1 L round-bottom flask. Thereaction mixture was cooled with an ice-bath under nitrogen. Bromine(25.62 mL, 0.5 mmol) was added dropwise over 30 minutes. The mixture wasfiltered and carefully added to NaOEt (21%, 412 mL, 1.11 mmol) in anice-cooled bath. The mixture was stirred at room temperature overnight,and then 5% HCl (1 L) and ether (300 mL) were added. The aqueous phasewas extracted with ether (2×300 mL). The combined organic phase waswashed with water, dried and concentrated. The residue was added to awarmed solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5g) in water (300 mL). Then boiling ethanol (300 mL) was added to give aclear solution. The mixture was refluxed for 2.5 hours and then stirredat room temperature overnight. The mixture was treated with water (1 L)and ether (300 mL). The aqueous phase was extracted with ether (2×300mL). The combined organic phase was washed with water, dried andconcentrated. The residue was purified by vacuum distillation (73-76° C.at 0.8 mm Hg) to give (2R)-ethyl2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (63 g, 64%). ¹H NMR(CDCl₃, 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J=16 Hz, 0.5H), 2.93 (m,0.5H), 2.50-2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05(m, 6H).

Step 5:

(2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (24 g,0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. with dryice/isopropanol. Ozonized oxygen (5-7 ft³h⁻¹ of O₂) was bubbled throughthe solution for 3.5 hours. The reaction mixture was flushed withnitrogen at room temperature until the color disappeared. The ethylacetate was removed under vacuum, and the residue was dissolved inacetic acid (150 mL) and cooled by ice water. Zinc powder (45 g) wasthen added. The solution was stirred for 30 minutes and then filtered.The filtrate was neutralized with 2N NaOH (1.3 L) and NaHCO₃. Theaqueous phase was extracted with ether (3×200 mL). The organic phase wascombined, washed with water, dried and concentrated to afford (2R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). ¹H NMR (CDCl₃, 400MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10(m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).

Step 6:

KOH (8.3 g, 147.9 mmol) in water (60 mL) was added to a solution of amixture of (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5mmol) and thiourea (9.2 g, 120.9 mmol) in ethanol (100 mL). The mixturewas refluxed for 10 hours. After cooling, the solvent was removed, andthe residue was neutralized with concentrated HCl (12 mL) at 0° C. Themixture was then extracted with DCM (3×150 mL). The solvent was removed,and the residue was purified by silica gel chromatography, eluting withhexane/ethyl acetate (2:1) to give(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 56%). MS (APCI+) [M+H]⁺183.

Step 7:

Raney Nickel (15 g) and NH₄OH (20 mL) were added to a suspension of(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 65.8 mmol) in distilled water (100 mL). The mixture was refluxed for3 hours and then filtered. The filtrate was concentrated to afford(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.89 g, 99%).MS (APCI+) [M+H]⁺151.

Step 8:

A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(5.8 g, 38.62 mmol) in POCl₃ (20 mL) was refluxed for 5 minutes. ExcessPOCl₃ was removed under vacuum, and the residue was dissolved in DCM (50mL). The mixture was then added to saturated NaHCO₃ (200 mL). Theaqueous phase was extracted with DCM (3×100 mL), and the combinedorganic phases were dried and concentrated. The residue was purified bysilica gel chromatography, eluting with ethyl acetate to give(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18 g,49%). ¹H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m,1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).

Step 9:

(R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (46 mg,0.27 mmol, 1.1 eq.) was added to a solution of the tert-butyl2-(N-(4-chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate (100 mg,0.25 mmol) and Hunig's base (0.1 mL, 0.75 mmol, 3 eq.) in acetonitrile(3 mL). The resulting mixture was heated to 80° C. overnight. Thereaction mixture was diluted with H₂O and extracted with DCM, dried andconcentrated to yield (R)-tert-butyl2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamido)ethylcarbamate(40 mg, 30%). MS (ESI) m/e (M+H⁺) 529.

Step 10:

A solution of HCl/dioxane at 0° C. was added to (R)-tert-butyl2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamido)ethylcarbamate(40 mg, 0.075 mmol) in MeOH (1 mL). The reaction mixture was stirred at25° C. for 1 hour. After removal of the solvent, the crude product waspurified by preparative HPLC to afford(R)—N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide(32 mg, 90%). MS (ESI) m/e (M+H⁺) 429.2. ¹H NMR: δ=8.56 (s, 1H),δ=7.23-7.56 (dd, 4H), δ=4.51 (s, 2H), δ=3.97-4.19 (m, 4H), δ=3.70 (m,1H), δ=3.61 (m, 4H), δ=3.40-3.43 (t, 2H), δ=2.96-3.15 (m, 4H), δ=2.42(m, 1H), δ=1.89 (m, 1H), δ=1.21-1.22 (d, 3H).

Example 2

(R)—N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide

Step 1:

Ethyl pulegenate (130 g, 662 mmol) in EtOAc (900 mL) was cooled to −78°C. using a dry ice-isopropanol bath. This mixture was subjected toozonolysis until the reaction turned purple in color. At this point,ozone generation ceased, and the reaction was removed from the dry-icebath. Oxygen was bubbled through the reaction mixture until it turnedyellow. The reaction mixture was concentrated under vacuum, and theresulting residue was dissolved in glacial acetic acid (400 mL). Thesolution was cooled to 0° C., and Zn dust (65 g, 993 mmol) was addedportionwise over 30 minutes. The reaction was then allowed to stir for 2hours, at which point the reaction mixture was filtered through a pad ofcelite to remove the zinc dust. The acetic acid was neutralized to a pHof 7 with aqueous NaOH and NaHCO₃ and extracted with ether (3×800 mL).The combined organics were dried with brine, MgSO₄ and concentrated togive (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate as a liquid (107g, 95%).

Step 2:

Ammonium acetate (240.03 g, 3113.9 mmol) was added to a solution of(R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106.0 g, 622.78 mmol)in MeOH (1.2 L). The reaction mixture was stirred at room temperatureunder nitrogen for 20 hours, after which it was complete as judged byTLC and HPLC. The reaction mixture was concentrated to remove MeOH. Theresulting residue was dissolved in DCM, washed twice with H₂O, once withbrine, dried (Na₂SO₄), filtered, and concentrated to give (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (102 g, 97% yield) as an oil.LC/MS (APCI+) m/z 170 [M+H]+.

Step 3:

A solution containing (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (161.61 g, 955.024 mmol) andammonium formate (90.3298 g, 1432.54 mmol) in formamide (303.456 ml,7640.19 mmol) was heated to an internal temperature of 150° C. andstirred for 17 hours. The reaction mixture was cooled, and transferredto a 2 L single nextracted flask. Then excess formamidine was removed byhigh vacuum distillation. Once formamidine stopped coming over, theremaining oil in the still pot was dissolved in DCM and washed withbrine (3×200 mL). The combined aqueous washes were extracted with DCM.The combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated. The resulting brown oil was dissolved in minimal DCM, andthis solution was added using a separatory funnel to a stirred solutionof ether (ca. 5 vol of ether vs. DCM solution), causing some brownprecipitate to form. This brown precipitate was removed by filtrationthrough a medium fit funnel which was rinsed with ether and disposed.The filtrate was concentrated, the trituration from ether repeated twomore times and then dried on high vacuum line to give(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (93.225 g,65.00% yield) as a pasty solid. LC/MS (APCI−) m/z 149.2.

Step 4:

Neat POCl₃ (463.9 ml, 5067 mmol) was added slowly by addition funnel toa 0° C. solution of(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013mmol) in DCE (1.2 L). After the addition was complete, the reactionmixture was warmed to room temperature, then heated to reflux andstirred for 70 minutes. The reaction was complete as determined by HPLC.The reaction mixture was cooled to room temperature, and the excessPOCl₃ was quenched in 4 portions as follows: Reaction mixturetransferred to separatory funnel and dripped into a beaker containingice and saturated NaHCO₃ solution cooled in an ice bath. Once theaddition of each portion of the reaction mixture was completed, thequenched mixture was stirred for 30 minutes to ensure completedestruction of POCl₃ prior to transfer to separatory funnel. The mixturewas transferred to the separatory funnel and extracted twice with DCM.The combined extracts were dried (Na₂SO₄), filtered, and concentrated.The crude was purified on silica gel as follows: silica gel (1 kg) wasslurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silicasettled under vacuum, topped with sand. The crude was loaded with aDCM/hexane mixture, and the compound was eluted using 1 L sidearm flasksunder vacuum. High Rf byproducts eluted first, then(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g,61.09% yield) as an oil.

Step 5:

4-Chloro-aniline (0.5 g, 3.9 mmol) was added to a solution of2-bromo-N,N-diethylethylamine hydrobromide (1.12 g, 4.3 mmol) andN,N-diisopropylethylamine (2 mL, 11.7 mmol) in toluene (7.8 mL). Themixture was stirred at room temperature for 5 hours. The mixture wasthen diluted with EtOAc (30 mL) and saturated NaHCO₃ (20 mL). Theorganic layer was washed with H₂O (1×20 mL), dried (Na₂SO₄), filteredand concentrated to give 4-chloro-N-(2-(diethylamino)ethyl)benzenamineas an oil which was used without purification. MS (APCI+) [M+H]⁺227.3.

Step 6:

tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (0.97 g, 3.9 mmol)was added to a solution of 4-chloro-N-(2-(diethylamino)ethyl)benzenamine(884 mg, 3.9 mmol) and N,N-diisopropylethylamine (1.9 mL, 11.7 mmol) inDCM (8 mL). The reaction mixture was heated at reflux for 20 hours. Themixture was cooled to room temperature, quenched with saturated NH₄Cl(10 mL), and extracted with DCM (2×20 mL). The combined organics weredried (Na₂SO₄), filtered and concentrated. The crude product waspurified by silica gel chromatography to give tert-butyl4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate(311 mg, 18%). MS (APCI+) [M+H]⁺439.4. ¹H NMR (CDCl₃, 400 MHz) δ□7.29(d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 3.70-3. 66 (m, 2H), 3.45-3.42(m, 2H), 3.24-3.21 (m, 4H), 3.15-3.12 (m, 2H), 2.61-2.57 (m, 2H), 2.52(q, J=7.2 Hz, 4H), 1.42 (s, 9H), 0.99 (t, J=7.2 Hz, 6H).

Step 7:

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate(311 mg, 0.7 mmol) in DCM (5 mL). The mixture was stirred at roomtemperature for 3 hours, and then concentrated in vacuo. The residue wasdissolved in n-butanol (2 mL). N,N-Diisopropylethylamine (0.5 mL, 3.6mmol) was added followed by(R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidine (113 mg,0.84 mmol). The reaction mixture was heated at 80° C. for 16 hours. Themixture was then diluted with H₂O, and extracted with DCM (2×20 mL). Thecombined organics were dried (Na₂SO₄), filtered and concentrated. Thecrude product was purified by preparative HPLC to giveN-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-4-((R)-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide(39.9 mg, 12%). MS (APCI+) [M+H]⁺471.3. ¹H NMR (CDCl₃, 400 MHz) δ□: 8.49(s, 1H), 7.40-7.35 (m, 2H), 7.17-7.13 (m, 2H), 4.06-3.95 (m, 4H),3.77-3.70 (m, 2H), 3.51-3.44 (m, 1H), 3.39-3.02 (m, 11H), 2.42-2.32 (m,1H), 1.88-1.82 (m, 1H), 1.33 (t, J=7.2 Hz, 6H), 1.15 (d, J=6.8 Hz, 3H).

Example 3

N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide

Step 1:

(R)-(+)-Pulegone (76.12 g, 0.5 mmol), anhydrous NaHCO₃ (12.5 g) andanhydrous ether (500 mL) were added to a 1 L round-bottom flask. Thereaction mixture was cooled with an ice-bath under nitrogen. Bromine(25.62 mL, 0.5 mmol) was added dropwise over 30 minutes. The mixture wasfiltered and carefully added to NaOEt (21%, 412 mL, 1.11 mmol) in anice-cooled bath. The mixture was stirred at room temperature overnight,and then 5% HCl (1 L) and ether (300 mL) were added. The aqueous phasewas extracted with ether (2×300 mL). The combined organic phase waswashed with water, dried and concentrated. The residue was added to awarmed solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5g) in water (300 mL), and then boiling ethanol (300 mL) was added togive a clear solution. The mixture was refluxed for 2.5 hours and thenstirred at room temperature overnight. The mixture was treated withwater (1 L) and ether (300 mL). The aqueous phase was extracted withether (2×300 mL). The combined organic phase was washed with water,dried and concentrated. The residue was purified by vacuum distillation(73-76° C. at 0.8 mm Hg) to give (2R)-ethyl2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (63 g, 64%). ¹H NMR(CDCl₃, 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J=16 Hz, 0.5H), 2.93 (m,0.5H), 2.50-2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05(m, 6H).

Step 2:

(2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (24 g,0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. with dryice/isopropanol. Ozonized oxygen (5-7 ft³h⁻¹ of O₂) was bubbled throughthe solution for 3.5 hours. The reaction mixture was flushed withnitrogen at room temperature until the color disappeared. The ethylacetate was removed under vacuum, and the residue was dissolved inacetic acid (150 mL) and cooled by ice water. Zinc powder (45 g) wasthen added. The solution was stirred for 30 minutes and then filtered.The filtrate was neutralized with 2N NaOH (1.3 L) and NaHCO₃. Theaqueous phase was extracted with ether (3×200 mL). The organic phase wascombined, washed with water, dried and concentrated to afford (2R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). ¹H NMR (CDCl₃, 400MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10(m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).

Step 3:

KOH (8.3 g, 147.9 mmol) in water (60 mL) was added to a solution of amixture of (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5mmol) and thiourea (9.2 g, 120.9 mmol) in ethanol (100 mL). The mixturewas refluxed for 10 hours. After cooling, the solvent was removed andthe residue was neutralized with concentrated HCl (12 mL) at 0° C. andthen extracted with DCM (3×150 mL). The solvent was removed, and theresidue was purified by silica gel chromatography, eluting withhexane/ethyl acetate (2:1) to give(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 56%). MS (APCI+) [M+H]⁺183.

Step 4:

Raney Nickel (15 g) and NH₄OH (20 mL) was added to a suspension of(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 65.8 mmol) in distilled water (100 mL). The mixture was refluxed for3 hours and then filtered. The filtrate was concentrated to afford(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.89 g, 99%).MS (APCI+) [M+H]⁺151.

Step 5:

A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(5.8 g, 38.62 mmol) in POCl₃ (20 mL) was refluxed for 5 minutes. Theexcess POCl₃ was removed under vacuum, and the residue was dissolved inDCM (50 mL). The mixture was then added to saturated NaHCO₃ (200 mL).The aqueous phase was extracted with DCM (3×100 mL), and the combinedorganic phases were dried and concentrated. The residue was purified bysilica gel chromatography, eluting with ethyl acetate to give(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18 g,49%). ¹H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m,1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).

Step 6:

m-CPBA (8.30 g, 37.0 mmol) was added in three portions to a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g,14.8 mmol) in CHCl₃ (60 mL). The mixture was stirred at room temperaturefor 2 days. The mixture was cooled to 0° C., and Na₂S₂O₃ (10 g) in water(60 mL) was added dropwise. Na₂CO₃ (6 g) in water (20 mL) was thenadded. The reaction mixture was stirred for 20 minutes. The aqueousphase was extracted with CHCl₃ (2×200 mL), and the combined organicphases were concentrated at low temperature (<25° C.). The residue waspurified by silica gel chromatography, eluting with ethylacetate-DCM/MeOH (20:1) to give(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45g, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H), 3.20 (m,2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).

Step 7:

A solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2hours. After cooling, excess solvent was removed under vacuum. Theresidue was purified by silica gel chromatography, eluting withhexane/ethyl acetate (3:1) to give(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.25 g, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03(m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d,J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS(APCI+) [M+H]⁺227.

Step 8:

(5R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate was converted into(5R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidin-7-ol bytreatment with LiOH in H₂O/THF, followed by an acidic workup (2N HCl inwater) to remove the acetate group.

Step 9:

4-Chlorobenzylamine (1.0 mL, 8.2 mmol) was added to a solution of2-bromo-N,N-diethylethylamine hydrobromide (2.4 g, 9.0 mmol) andtriethylamine (3.4 mL, 25 mmol) in dichloromethane (16 mL). The mixturewas stirred at room temperature for 5 hours. The mixture was thenconcentrated to give N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamineas an oil which was used immediately without purification.

Step 10:

tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (245 mg, 0.99 mmol)was added to a solution ofN1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine (235 mg, 0.98 mmol)and N,N-diisopropylethylamine (0.54 mL, 2.94 mmol) in DCM (2 mL). Thereaction mixture was allowed to stir at room temperature for 1 hour. Themixture was quenched with saturated NH₄Cl (2 mL) and extracted with DCM(2×5 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by silica gelchromatography to give tert-butyl4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate(200 mg, 45%). ¹H NMR (CDCl3, 400 MHz) δ□7.32 (d, J=8.4 Hz, 2H), 7.19(d, J=8.4 Hz, 2H), 4.42 (s, 2H), 3.45-3.40 (m, 4H), 3.25-3.20 (m, 4H),3.18 (t, J=6.8 Hz, 2 Hz), 2.56 (t, J=6.8 Hz, 2H), 2.49 (q, J=7.2 Hz,4H), 1.46 (s, 9H), 0.99 (t, J=7.2 Hz, 6H).

Step 11:

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl4-(N-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate(88 mg, 0.19 mmol) in DCM (1 mL). The mixture was stirred at roomtemperature for 3 hours, and then concentrated in vacuo. The residue wasdissolved in n-butanol (1 mL). N,N-diisopropylethylamine (0.11 mL, 0.6mmol) was added to the solution. Then,(5R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidin-7-ol (37mg, 0.20 mmol) was added to the solution. The reaction mixture washeated at 80° C. for 16 hours. The mixture was then diluted with H₂O (1mL), and extracted with DCM (2×5 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude product was purified bypreparative HPLC to giveN-(4-chlorobenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide(19.9 mg, 21%). MS (APCI+) [M+H]+501.3. ¹H NMR (CDCl3, 400 MHz) δ□8.46(s, 1H), 7.34 (d, J=8.4 Hz, 4H), 7.13 (d, J=8.4 Hz, 4H), 5.50 (t, J=8Hz, 1H), 5.28 (dd, J=3.6, 8.4 Hz, 1H), 4.45 (s, 4H), 4.14-4.04 (m, 4H),3.94-3.81 (m, 4H), 3.51-3.42 (m, 8H), 3.20-3.00 (m, 16H), 2.73-2.64 (m,2H), 2.40-2.20 (m, 4H), 2.05-1.98 (m, 1H), 1.86-1.78 (m, 1H), 1.33 (d,J=7.2 Hz, 3 Hz), 1.28 (t, J=7.2 Hz, 12H), 1.21 (d, J=6.8 Hz, 3 Hz).

Examples 4-14 shown in Table 1 can also be made according to the abovedescribed methods.

TABLE 1 Example Structure Name LCMS  4

(R)-N-(2-aminoethyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-(4-(trifluoromethylthio)benzyl)piperazine- 1-carboxamide 495    5

(R)-N-(2-aminoethyl)-N-(2,4- dichlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-1-carboxamide 463.1 6

(R)-N-(2-aminoethyl)-N-(4- iodobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-1-carboxamide 521.1  7

(R)-N-(2-aminoethyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-(4-(trifluoromethoxy)benzyl)piperazine-1- carboxamide 479.2  8

(R)-N-(2-aminoethyl)-N-(4- fluorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-1-carboxamide 413.2 9

(R)-N-(2-aminoethyl)-N-(4- bromobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-1-carboxamide 473.110

(R)-N-(2-aminoethyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-(4-(trifluoromethyl)benzyl)piperazine-1- carboxamide 463   11

(R)-N-(2-aminoethyl)-N-(4-chloro-3- fluorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-1-carboxamide 447.112

(R)-N-(2-aminoethyl)-N-(3,4- dichlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-1-carboxamide 463.113

(R)-N-(4-chlorobenzyl)-N-(2- (diethylamino)ethyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazine-1-carboxamide 485.314

(R)-N-(2-aminoethyl)-N-((5- bromothiophen-2-yl)methyl)-4-(5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide 479   15

N-(4-chloro-3-fluorobenzyl)-4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-((R)-pyrrolidin-3-yl)piperazine- 1-carboxamide 489.2 16

N-(4-chloro-3-fluorobenzyl)-4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-((S)-pyrrolidin-3-yl)piperazine- 1-carboxamide 489.2 17

N-(4-chloro-3-fluorobenzyl)-4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-(piperidin-4-yl)piperazine-1-carboxamide 503.2 18

N-(azetidin-3-yl)-N-(4-chloro-3- fluorobenzyl)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide 475.2 19

N-(2-aminoethyl)-N-(4-chloro-3- fluorobenzyl)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide 463.2 20

N-(4-chloro-3-fluorobenzyl)-4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-(2-(isopropylamino)ethyl)piperazine-1- carboxamide 505.3

While the invention has been described in conjunction with theenumerated embodiments, it will be understood that they are not intendedto limit the invention to those embodiments. On the contrary, theinvention is intended to cover all alternatives, modifications andequivalents, which may be included within the scope of the presentinvention as defined by the claims. Thus, the foregoing description isconsidered as illustrative only of the principles of the invention.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

What is claimed is:
 1. A method of treating an AKT-mediated disease ordisorder in a mammal, said method comprising administering to saidmammal an effective amount of a compound of Formula I:

or an enantiomer or salt thereof, wherein: R¹ and R^(1a) areindependently selected from H, Me, Et, vinyl, CF₃, CHF₂ or CH₂F; R² isH, OH, OMe or F; R^(2a) is H, Me or F; R³ is H, Me, Et, or CF₃; A is

G is phenyl optionally substituted by one to four R^(e) groups or a 5-6membered heteroaryl optionally substituted by a halogen; R⁵ and R⁶ areindependently H, OCH₃, C₃-C₆-cycloalkyl optionally substituted with F,OH, C₁-C₃ alkyl or O(C₁-C₃ alkyl), 4-6 membered heterocycle optionallysubstituted with F, OH, C₁-C₃ alkyl, cyclopropylmethyl or C(═O)(C₁-C₃alkyl), or C₁-C₆-alkyl optionally substituted with one or more groupsindependently selected from OH, oxo, O(C₁-C₆-alkyl), CN, F, NH₂,NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl,piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl ortetrahydropyranyl, or R⁵ and R⁶ together with the nitrogen to which theyare attached form a 4-7 membered heterocyclic ring optionallysubstituted with one or more groups independently selected from OH,halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH, O(C₁-C₃ alkyl), C(═O)CH₃, NH₂,NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃ alkyl, or R^(c) ishydrogen and R^(d) and R⁶ together with the atoms to which they areattached form a 4 to 6 membered heterocyclic ring having one nitrogenatom; R^(a) and R^(b) are H, or R^(a) is H, and R^(b) and R⁶ togetherwith the atoms to which they are attached form a 5-6 memberedheterocyclic ring having one or two ring nitrogen atoms; R^(c) and R^(d)are H or Me, or R^(c) and R^(d) together with the atom to which they areattached from a cyclopropyl ring; each R^(e) is independently halogen,C₁-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃, OCF₃, S(C₁-C₆-alkyl), CN,OCH₂-phenyl, NH₂, NO₂, NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine,pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂,C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂; m and n are independently0, 1, 2 or 3 with the proviso that (m+n) must equal 2, 3 or 4; and p is0 or
 1. 2. The method of claim 1 wherein: R¹ and R^(1a) areindependently selected from H, Me, Et, vinyl, CF₃, CHF₂ or CH₂F; R² isH, OH, OMe or F; R^(2a) is H, Me or F; R³ is H, Me, Et, or CF₃; A is

G is phenyl optionally substituted by one to four R^(e) groups or a 5-6membered heteroaryl optionally substituted by a halogen; R⁵ and R⁶ areindependently H, OCH₃, C₃-C₆-cycloalkyl optionally substituted with F,OH, C₁-C₃ alkyl or O(C₁-C₃ alkyl), 4-6 membered heterocycle optionallysubstituted with F, OH, C₁-C₃ alkyl, cyclopropylmethyl or C(═O)(C₁-C₃alkyl), or C₁-C₆-alkyl optionally substituted with one or more groupsindependently selected from OH, oxo, O(C₁-C₆-alkyl), CN, F, NH₂,NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl,piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl ortetrahydropyranyl, or R⁵ and R⁶ together with the nitrogen to which theyare attached form a 4-7 membered heterocyclic ring optionallysubstituted with one or more groups independently selected from OH,halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH, O(C₁-C₃ alkyl), C(═O)CH₃, NH₂,NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃ alkyl; R^(a) andR^(b) are H, or R^(a) is H, and R^(b) and R⁶ together with the atoms towhich they are attached form a 5-6 membered heterocyclic ring having oneor two ring nitrogen atoms; R^(c) and R^(d) are H or Me, or R^(c) andR^(d) together with the atom to which they are attached from acyclopropyl ring; each R^(e) is independently halogen, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, O—(C₁-C₆-alkyl), CF₃, OCF₃, S(C₁-C₆-alkyl), CN,OCH₂-phenyl, NH₂, NO₂, NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine,pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂,C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂; m and n are independently0, 1 or 2, with the proviso that (m+n) must equal 2, 3 or 4; and p is 0or
 1. 3. The method of claim 1 wherein R³ is H.
 4. The method of claim 1wherein R³ is methyl.
 5. The method of claim 4, wherein said methyl isoptionally in the (S) configuration.
 6. The method of claim 1 wherein R³is ethyl.
 7. The method of claim 1 wherein R¹ is methyl.
 8. The methodof claim 7, wherein said methyl is optionally in the (R) configuration.9. The method of claim 1 wherein R¹ is hydrogen.
 10. The method of claim1 wherein R^(1a) is hydrogen.
 11. The method of claim 1 wherein R^(1a)is methyl.
 12. The method of claim 1 wherein R² is H.
 13. The method ofclaim 1 wherein R² is F.
 14. The method of claim 1 wherein R² is OH. 15.The method of claim 1 wherein R^(2a) is H.
 16. The method of claim 1wherein R^(2a) is F.
 17. The method of claim 1 wherein G is phenyloptionally substituted with one to four R^(e) groups.
 18. The method ofclaim 17, wherein G is phenyl optionally substituted with one to fourgroups independently selected from F, Cl, Br, I, methyl, ethyl,isopropyl, tert-butyl, cyclopropyl, CN, CF₃, OMe, OEt, OCF₃, NO₂, SMeand OCH₂Ph.
 19. The method of claim 18, wherein G is 4-chlorophenyl,4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl,4-trifluormethoxyphenyl, 4-thiomethylphenyl, 3-fluoro-4-chlorophenyl,2,4-dichlorophenyl or 3,4-dichlorophenyl.
 20. The method of claim 1,wherein G is a 5-6 membered monocyclic heteroaryl optionally substitutedby one or more halogens.
 21. The method of claim 20, wherein G is:


22. The method of claim 1 wherein R^(a) is H.
 23. The method of claim 1wherein R^(b) is H.
 24. The method of claim 1 wherein R^(c) is H. 25.The method of claim 1 wherein R^(d) is H.
 26. The method of claim 1wherein R⁵ is H or ethyl.
 27. The method of claim 1 wherein R⁶ is H orethyl.
 28. The method of claim 1 wherein m is 1 and n is
 1. 29. Themethod of claim 1 wherein p is
 0. 30. The method of claims 29, wherein Ais:


31. The method of claim 1 wherein p is
 1. 32. The method of claim 31,wherein A is:


33. The method of claim 31, wherein A is:


34. The method of claim 1, wherein m is 0, R^(c) is hydrogen, and R^(d)and R⁶ together with the atoms to which they are attached form a 4 to 6membered heterocyclic ring having one nitrogen atom.
 35. The method ofclaim 34, wherein n is 1 and q is 1, n is 1 and q is 2, or n is 2 and qis
 2. 36. The method of claim 1 wherein said disease or disorder isinflammatory, hyperproliferative, cardiovascular, neurodegenerative,gynecological, or dermatological disease.
 37. A method of inhibiting theproduction of AKT protein kinase in a mammal, which comprisesadministering to said mammal an effective amount of a compound asdescribed in claim 1.